Neuregulin-1 (NRG-1) was genetically identified as a schizophrenia susceptibility gene, but its function in the adult brain is unknown. Our present knowledge of NRG-1 as a trophic and differentiation factor in the peripheral and central nervous system is mostly restricted to early development. Although NRG-1 and its ErbB tyrosine kinase receptors (ErbB 1-4) are expressed in the adult rodent and human brain, little is known about their functions. NRG-1 is expressed in the hippocampus, and is processed and released at synapses in an activity-dependent manner. In adult brain, we showed that ErbB receptors colocalize with NMDARs at glutamatergic postsynaptic sites and interact with PDZ-domain scaffolding proteins, which are important for remodeling synapses in response to activity. Based on these findings, we proposed that NRG signaling had the potential to rapidly modulate synaptic plasticity in response to activity. Our present work supports this hypothesis. We found that while NRG-1 has no effect on basal glutamatergic synaptic transmission, it reverses long-term potentiation (LTP) at hippocampal CA1 synapses in an activity-dependent fashion. Interestingly, the potential of NRG-1 to reverse (depotentiate) LTP is time-dependent, it only works within the first 30 min after eliciting LTP. We found that ErbB inhibitors block NRG-1, as well as stimulus-dependent, reversal of LTP, and also increase LTP levels at potentiated synapses. Using patch clamp and cell biological techniques, we demonstrated that NRG-1 depotentiates LTP by selectively reducing AMPA, but not NMDA, receptor currents. Live imaging of hippocampal neurons transfected with receptors fused to superecliptic green fluorescent protein (seGFP), a form of GFP that only fluoresces strongly when expressed on the cell surface, indicate that NRG-1 stimulates the internalization of surface GluR1-containing AMPA receptors. This novel regulation of LTP by NRG-1 has important implications for the modulation of synaptic homeostasis at glutamatergic synapses, and for understanding molecular mechanisms that underlie complex disorders like schizophrenia. B. ACTIVITY-DEPENDENT REGULATION OF MUSCLE TYPES Skeletal muscle size and contractile properties are modified by exercise. The different patterns of electrical impulses elicited during distinct types of exercise regulate muscle mass, and their slow- and fast-twitch contractile properties. Our long-term objective is to identify the signaling pathways that regulate the properties of slow- and fast-twitch muscles in response to activity. The troponin I slow (TnIs) and fast (TnIf) genes have served as our experimental model because expression of both genes is regulated by either slow or fast patterns of electrical impulses, similar to those produced by slow- or fast-firing motor neurons. We have identified the slow upstream regulatory enhancer (SURE) and the fast intronic regulatory element (FIRE) as minimal DNA sequences that regulate the fiber-type-specific transcription of the TnIs and TnIf genes, respectively. Interestingly, the SURE element is bipartite: the downstream half regulates muscle specificity and the upstream half is necessary for fiber-type specificity. We found that the General Transcription Factor 3 (GTF3) binds to a site in the upstream half of SURE. Using a method to select transcription factor DNA binding sites from random pools of sequences, we determined that (G/A)GATT(A/G) is the GTF3 consensus site and is located in the TnI SURE (and other enhancers reported to be regulated by GTF3). The GTF3 DNA binding domain was mapped to helix motif 4, which is necessary and sufficient to bind the TnI SURE. Interestingly, GTF3 is lost in a ~2.0 Mb micro-deletion of chromosome 7q11.2 in individuals with Williams Syndrome (WS). Persons with WS have distinctive physical, cognitive and behavior abnormalities that include impaired spatial cognitive skills and myopathies. Our studies using ectopically transfected GTF3 constructs in adult muscles and GTF3 knock-out mice support a possible role for this factor in regulating muscle contractile properties. Slow and fast motor neuron firing properties activate the transcription of genes expressed in either slow- or fast-twitch muscles. The mechanisms responsible for sensing and decoding distinct patterns of action potentials, and converting them into specific changes in gene expression, remain unknown. Using the TnIs and TnIf enhancers as reporter constructs driving expression of the green fluorescent protein (GFP), we found that stimulation of muscles with either slow or fast patterns of electrical stimuli differentially regulate these enhancers. Slow, tonic patterns of depolarization upregulate the SURE, while fast, phasic patterns increase FIRE transcription. These results indicate that the TnI slow and fast enhancers can sense, and respond to, distinct patterns of neuronal activity. Experiments are in progress to identify the specific SURE and FIRE DNA regulatory elements that differentially respond to activity, and the signal transduction pathways that mediate these effects.